Skip to content

Advertisement

You're viewing the new version of our site. Please leave us feedback.

Learn more
Open Access

Antihypertrophic actions of NO-independent soluble guanylyl cyclase (sGC) ligands BAY 41-2272 and BAY 58-2667 in vitro

  • Rebecca Ritchie1Email author,
  • Jennifer Irvine1,
  • Jane Love1,
  • John Horowitz3,
  • Johannes-Peter Stasch4 and
  • Barbara Kemp-Harper2
BMC Pharmacology20099(Suppl 1):P59

https://doi.org/10.1186/1471-2210-9-S1-P59

Published: 11 August 2009

Background

Over the last decade, we have shown that cGMP, derived from bradykinin, nitric oxide (NO, both from endogenous and exogenous sources) or natriuretic peptides, is a potent inhibitor of cardiac hypertrophy, across isolated cardiomyocytes and intact hearts both ex vivo and in vivo. However, NO• bioavailability is reduced due to scavenging by ROS; furthermore, oxidation of sGC may result in sGC dysfunction (including loss of responsiveness to NO•). In the present study, we tested the hypothesis that the NO•-independent sGC stimulator BAY 41-2272 and the NO-independent sGC activator BAY 58-2667 elicit powerful antihypertrophic actions.

Materials and methods

Neonatal rat cardiomyocytes were incubated at 37°C in the presence of the hypertrophic stimulus, endothelin-1 (ET1, 60 nM) ± BAY 41-2272 or BAY 58-2667 (0.01–0.3 μM) for 48 h in serum-free conditions. Cardiomyocyte hypertrophy was assessed in live cells using conventional in vitro markers of hypertrophy, two dimensional area and cardiomyocyte de novo protein synthesis. Results were expressed as % paired control cardiomyocytes, mean ± SE.

Results

See Table 1.
Table 1

sGC ligands inhibit cardiomyocyte hypertrophy

 

Control

ET1 alone

ET1 + BAY (0.01 μM)

ET1 + BAY (0.03 μM)

ET1 + BAY (0.10 μM)

ET1 + BAY (0.30 μM)

Cell size (% paired control cardiomyocytes, both n = 4)

BAY 41-2272

100 ± 0%

146 ± 9%*

128 ± 5%#

116 ± 7%#

106 ± 6%#

108 ± 6%#

BAY 58-2667

100 ± 0%

141 ± 8%*

133 ± 11%

123 ± 7%#

113 ± 2%#

108 ± 12%

De novo protein synthesis (% paired control cardiomyocytes, n = 5–6)

BAY 41-2272

100 ± 0%

122 ± 1%*

102 ± 1%#

101 ± 1%#

102 ± 2%#

110 ± 0%#

BAY 58-2667

100 ± 0%

135 ± 2%*

110 ± 3%

117 ± 3%

107 ± 2%#

108 ± 3%

*p < 0.05 versus control; #p < 0.05 versus ET1, on one-way RM. DMSO, the vehicle for the sGC ligands, had no effect on either parameter either alone, or in the presence of ET1.

Conclusion

These results provide evidence that BAY 41-2272 and BAY 58-2667 elicit concentration-dependent inhibition of cardiac hypertrophy in vitro, in the absence of confounding haemodynamic factors and even at low (submicromolar) concentrations. These novel NO•-independent sGC ligands thus potentially may serve as useful antihypertrophic agents in patients, independent of blood pressure.

Authors’ Affiliations

(1)
Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute
(2)
Department of Pharmacology, Monash University
(3)
Cardiology Unit, The Queen Elizabeth Hospital
(4)
Bayer HealthCare AG, Pharma Research Center

Copyright

© Ritchie et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

Advertisement